From the WO 93/22678, a method and an apparatus are known for identifying molecular structures within a sample using a monolithic array of test sites formed on a substrate. Each test site includes probes for bonding with a predetermined molecular target, wherein said probes have been fixed during the manufacture of the apparatus by selectively heating the test site with a laser beam or with an integrated heating element.
Based on this situation it was an object of the present invention to provide means for a more versatile temperature controlled investigation of a sample in a microelectronic sensor device.
This objective is achieved by a microelectronic sensor device according to claim 1 and a use according to claim 36. Preferred embodiments are disclosed in the dependent claims.
The microelectronic sensor device according to the present invention is intended for the investigation of a sample, particularly a liquid or gaseous chemical substance like a biological body fluid which may contain particles. It comprises the following components:    a) A sample chamber in which the sample to be investigated can be provided. The sample chamber is typically an empty cavity or a cavity filled with some substance like a gel that may absorb a sample substance; it may be an open cavity, a closed cavity, or a cavity connected to other cavities by fluid connection channels.    b) A “sensing array” that comprises a plurality of sensor elements for sensing properties of a sample in the sample chamber, for example the concentration of particular target molecules in a fluid. In the most general sense, the term “array” shall in the context of the present invention denote an arbitrary three-dimensional arrangement of a plurality of elements (e.g. the sensor elements). Typically such an array is two-dimensional and preferably also planar, and the (sensor) elements are arranged in a regular pattern, for example a grid or matrix pattern.
Furthermore, it should be noted that a “heat exchange with a sub-region of the sample chamber” is assumed if such an exchange is strong enough in the sub-region to provoke desired/observable reactions of the sample. This definition shall exclude small “parasitic” thermal effects that are inevitably associated with any active process, e.g. with electrical currents. Typically, a heat flow in the sense of the present invention is larger than 0.01 W/cm2 and will have a duration in excess of 1 millisecond.    c) A “heating array” that comprises a plurality of heating elements for exchanging heat with at least a sub-region of the sample chamber when being driven with electrical energy. The heating elements may preferably convert electrical energy into heat that is transported into the sample chamber. It is however also possible that the heating elements absorb heat from the sample chamber and transfer it to somewhere else under consumption of electrical energy.    d) A control unit for selectively driving the heating elements (i.e. for supplying electrical energy to them) during or prior to the sensing of a sample in the sample chamber.
The aforementioned microelectronic sensor device has the advantage that the sample chamber can at the same time be investigated by the sensor elements and temperature-controlled via the heating elements. This allows to establish optimal temperature conditions in the sample chamber during a measurement, thus improving the accuracy of tests significantly or even making certain tests possible at all.
The control unit is preferably adapted to drive the heating elements such that a desired spatial and/or temporal temperature profile is achieved in the sample chamber. This allows to provide optimal (particularly non-uniform and/or dynamic) conditions for the manipulation of e.g. a sensitive biological sample.
According to a preferred embodiment of the microelectronic sensor device, the heating elements are aligned with respect to the sensor elements. This “alignment” means that there is a fixed (translation-invariant) relation between the positions of the heating elements in the heating array and the sensor elements in the sensing array; the heating and sensor elements may for example be arranged in pairs, or each heating element may be associated with a group of several sensor elements (or vice versa). The alignment has the advantage that the heating and sensor elements interact similarly at different locations. Thus uniform/periodic conditions are provided across the arrays.
A preferred kind of alignment between the sensor and the heating elements is achieved if the patterns of their arrangement in the sensing array and the heating array, respectively, are identical. In this case, each sensor element is associated with just one heating element.
In an alternative embodiment, more than one heating element is associated to each sensor element. This allows to create a spatially non-uniform heating profile, which can result in either a spatially non-uniform or a spatially uniform temperature profile in the region of one sensor element and thus an even better temperature control. Preferably, there is additionally an alignment of the above mentioned kind between heating elements and sensor elements.
The sensing array may for example comprise optical, magnetic, mechanical, acoustic, thermal and/or electrical sensor elements. A microelectronic sensor device with magnetic sensor elements is for example described in the WO 2005/010543 A1 and WO 2005/010542 A2 (which are incorporated into the present text by reference). Said device is used as a microfluidic biosensor for the detection of biological molecules labeled with magnetic beads. It is provided with an array of sensor units comprising wires for the generation of a magnetic field and Giant Magneto Resistance devices (GMRs) for the detection of stray fields generated by magnetized beads. Moreover, optical, mechanical, acoustic, and thermal sensor concepts are described in the WO 93/22678, which is incorporated into the present text by reference.
According to one embodiment of the microelectronic sensor device, the heating array and the sensing array are disposed on opposite sides of the sample chamber. Such an arrangement can readily be combined with known designs of biosensors as only the cover of the sample chamber has to be replaced by the heating array.
In an alternative embodiment, the heating array and the sensing array are disposed on the same side of the sample chamber. In this case, the arrays may be arranged in a layered structure one upon the other, or they may be merged in one layer.
In the aforementioned embodiment with a layered structure, the sensing array is preferably disposed between the sample chamber and the heating array. Thus it will be as close as possible to the sample chamber which guarantees an optimal access to the sample.
The aforementioned arrangements of the heating array relative to the sample chamber and the sensing array can be combined if the heating array comprises two parts which are disposed on different (particularly opposite) sides of the sample chamber. Heating the sample chamber from opposite sides allows to create more uniform temperatures in it as well as to deliberately create temperature gradients directed e.g. from one of the sides to the other.
According to another embodiment of the microelectronic sensor device, the control unit is located outside the array of heating elements and connected to the heating elements by power lines that can selectively carry electrical energy to (or away from) the heating elements. As the amount or rate of transferred electrical energy determines the extent to which heat is exchanged with the sample chamber, the control unit has to allocate the transferred electrical energy appropriately in order to achieve a desired temperature profile in the sample chamber. The heating array can be kept most simple in this approach because the heating elements just have to convert electrical energy into heat without further processing, i.e. they may for example be realized by simple resistors.
In a further development of the aforementioned embodiment, the control unit comprises a de-multiplexer for coupling the control unit to the power lines. This allows to use one circuit for providing several power lines (subsequently) with electrical power.
According to another realization of the microelectronic sensor device, each heating element is associated with a local driving unit, wherein said driving units are geometrically located at (i.e. near) and coupled to the heating elements. Such local driving units can take over certain control tasks and thus relieve the control unit.
In a further development of the aforementioned embodiment, the local driving units are coupled to a common power supply line, and the heating elements are coupled to another common power supply line (e.g. ground). In this case each local driving unit determines the amount of electrical energy or power that is taken from the common power supply lines. This simplifies the design insofar as properly allocated amounts of electrical energy do not have to be transported through the whole array to a certain heating element.
In another embodiment of the microelectronic sensor device with local driving units, a part of the control unit is located outside the array of heating elements and connected via control lines for carrying control signals to the local driving units (which constitute the residual part of the control unit). In this case the outside part of the control unit can determine how much electrical energy or power a certain heating element shall receive; this energy/power needs however not to be transferred directly from the outside control unit to the heating element. Instead, only the associated information has to be transferred via the control signals to the local driving units, which may then extract the needed energy/power e.g. from common power supply lines.
In a preferred realization of the aforementioned embodiment, the control signals are pulse-width modulated (PWM). With such PWM signals, the local driving units can be switched off and on with selectable rate and duty cycle, wherein these parameters determine the average power extraction from common power supply lines. The individual characteristics of the local driving units are then less critical as only an on/off behavior is required.
In a further development of the embodiments with local driving units, said units comprise a memory for storing information of control signals transmitted by the outside part of the control unit. Such a memory may for example be realized by a capacitor that stores the voltage of the control signals. The memory allows to continue a commanded operation of a heating element while the associated control line is disconnected again from the driving unit and used to control other driving units.
In the embodiment with local driving units it often turns out in practice that even with an identical design of the driving units, the components and circuitry that make them up have statistical variations in their characteristics which lead to variations in the behavior of the driving units. Commanding different driving units with the same voltage may then for example lead to different results, e.g. distinct current outputs to the heating elements. This makes a precise control of temperature in the sample chamber difficult if not impossible. The microelectronic sensor device may therefore incorporate means for compensating variations in the individual characteristic values of the driving units. This allows a control with much higher accuracy.
In a typical design of the aforementioned microelectronic sensor device, at least one driving unit comprises a transistor which produces for a given input voltage V at its gate an output current I (which will be fed to the heating element) according to the formulaI=m·(V−Vthres)2,wherein m and Vthres are the individual characteristic values of the transistor. The formula illustrates that local driving units with different values of m and Vthres will behave differently when controlled with the same voltage.
In the aforementioned case, the driving units preferably each comprise a capacitor coupled to the control gate of said transistor and circuitry to charge this capacitor to a voltage that compensates Vthres or that drives the transistor to produce a predetermined current I. Thus the application of a simple capacitor may suffice to compensate individual variations in the very important case of driving units based on a transistor of the kind described above. Further details with respect to an associated circuitry will be described in connection with the Figures.
The heating elements may particularly comprise a resistive strip, a transparent electrode, a Peltier element, a radio frequency heating electrode, or a radiative heating (IR) element. All these elements can convert electrical energy into heat, wherein the Peltier element can additionally absorb heat and thus provide a cooling function.
The microelectronic sensor device may optionally comprise a cooling unit, e.g. a Peltier element or a cooled mass, in thermal contact with the heating array and/or with the sample chamber. This allows to reduce the temperature of the sample chamber if necessary. In combination with a heating array for the generation of heat, a cooling unit therefore enables a complete control of temperature in both directions.
While the heating elements are in most practical cases (only) capable of generating heat, at least one of them may optionally also be adapted to remove heat from the sample chamber. Such a removal may for example be achieved by Peltier elements or by coupling the heating elements to a heat sink (e.g. a mass cooled with a fan).
The microelectronic sensor device may optionally comprise at least one temperature sensor which makes it possible to monitor the temperature in the sample chamber. The temperature sensor(s) may preferably be integrated into the heating array. In a particular embodiment, at least one of the heating elements is designed such that it can be operated as a temperature sensor, which allows to measure temperature without additional hardware.
In cases in which a temperature sensor is available, the control unit is preferably coupled to said temperature sensor and adapted to control the heating elements in a closed loop according to a predetermined (temporal and/or spatial) temperature profile in the sample chamber. This allows to provide robustly optimal conditions for the manipulation of e.g. a sensitive biological sample.
The microelectronic sensor device may further comprise a micromechanical or an electrical device, for example a pump or a valve, for controlling the flow of a fluid and/or the movement of particles in the sample chamber. Controlling the flow of a sample or of particles is a very important capability for a versatile manipulation of samples in a microfluidic device.
In a particular embodiment, at least one of the heating elements may be adapted to create flow in a fluid in the sample chamber by a thermo-capillary effect. Thus its heating capability can be exploited for moving the sample.
If it is necessary or desired to have sub-regions of different temperature in the sample chamber, this may optionally be achieved by dividing the sample chamber with a heat insulation into at least two compartments. Particular embodiments of this approach will be described in more detail in connection with the Figures.
An electrically isolating layer and/or a biocompatible layer may be disposed between the sample chamber and the heating and/or sensing array. Such a layer may for example consist of silicon dioxide SiO2 or the photoresist SU8.
In a further embodiment of the invention, the control unit is adapted to drive the heating elements with an alternating current of selectable intensity and/or frequency. The electrical fields associated with such an operation of the heating elements may in certain cases, for example in cases of di-electrophoresis, generate a motion in the sample if they have an appropriate intensity and frequency. On the other hand, the intensity and frequency of the alternating current determines the average rate of heat production. Thus it is possible to execute a heating and a manipulation function with such a heating element simply by changing the intensity and/or frequency of the applied current appropriately.
The heating element(s) and/or field electrode(s) may preferably be realized in thin film electronics.
When realizing a microelectronic sensor device according to the present invention, a large area electronics (LAE) matrix approach, preferably an active matrix approach may be used in order to contact the heating elements and/or the sensor elements. The technique of LAE, and specifically active matrix technology using for example thin film transistors (TFTs) is applied for example in the production of flat panel displays such as LCDs, OLED and electrophoretic displays.
In the aforementioned embodiment, a line-at-a-time addressing approach may be used to address the heating elements by the control unit.
According to a further development of the microelectronic sensor device, the interface between the sample chamber and the heating and/or sensing array is chemically coated in a pattern that corresponds to the patterns of the heating elements and/or sensor elements, respectively. Thus the effect of these elements can be combined with chemical effects, for example with the immobilization of target molecules out of a sample solution at binding molecules which are attached to the interface.
The invention further relates to the use of the microelectronic sensor devices described above for molecular diagnostics, biological sample analysis, chemical sample analysis, food analysis, and/or forensic analysis. Molecular diagnostics may for example be accomplished with the help of magnetic beads or fluorescent particles that are directly or indirectly attached to target molecules.
Like reference numbers/characters in the Figures refer to identical or similar components.